Biodegradable poly(phosphoesters)

ABSTRACT

The invention relates to poly(phosphoesters), compositions comprising the poly(phosphoesters), and methods of use.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to poly(phosphoesters) and methods ofusing these polymers.

2. Description of the Background Art

Many polymeric materials have been used as components of devices fordiagnosis or therapy, and they have made a significant impact on theclinical success of implant technology. These materials have been usedas, for example, orthopedic devices, ventricular shunts, drug-carriers,contact lens', heart valves, sutures, and burn dressings. These polymerscan be non-biodegradable or biodegradable.

In traditional drug delivery, it has long been recognized that tablets,capsules, and injections may not be the best mode of administration.These conventional routes often involve frequent and repeated doses,resulting in a "peak and valley" pattern of therapeutic agentconcentration. Since each therapeutic agent has a therapeutic rangeabove which it is toxic and below which it is ineffective, a fluctuatingtherapeutic agent concentration may cause alternating periods ofineffectiveness and toxicity. For this reason, controlled releaseprovides a way of maintaining the therapeutic agent level within thedesired therapeutic range for the duration of treatment. Using apolymeric carrier is one effective means to deliver the therapeuticagent locally and in a controlled fashion (Langer, et al., Rev. Macro.Chem. Phys., C23(1), 61, 1983). As a result of less total drug required,systemic side effects can be minimized.

Polymers have been used as carriers of the therapeutic agents to effecta localized and sustained release (Controlled Drug Delivery, Vol. I andII, Bruck, S. Dak., (ed.), CRC Press, Boca Raton, Fla., 1983; Novel DrugDelivery Systems, Chien, Y. W., Marcel Dekker, New York, 1982). Thesetherapeutic agent delivery systems simulate infusion and offer thepotential of enhanced therapeutic efficacy and reduced systemictoxicity.

For a non-biodegradable matrix, the steps leading to release of thetherapeutic agent are water diffusion into the matrix, dissolution ofthe therapeutic agent, and outdiffusion of the therapeutic agent throughthe channels of the matrix. As a consequence, the mean residence time ofthe therapeutic agent existing in the soluble state is longer for anon-biodegradable matrix than for a biodegradable matrix where a longpassage through the channels is no longer required. Since manypharmaceuticals have short half-lives it is likely that the therapeuticagent is decomposed or inactivated inside the non-biodegradable matrixbefore it can be released. This issue is particularly significant formany bio-macromolecules and smaller polypeptides, since these moleculesare generally unstable in buffer and have low permeability throughpolymers. In fact, in a non-biodegradable matrix, manybio-macromolecules will aggregate and precipitate, clogging the channelsnecessary for diffusion out of the carrier matrix. This problem islargely alleviated by using a biodegradable matrix which allowscontrolled release of the therapeutic agent.

Biodegradable polymers differ from non-biodegradable polymers in thatthey are consumed or biodegraded during therapy. This usually involvesbreakdown of the polymer to its monomeric subunits, which should bebiocompatible with the surrounding tissue. The life of a biodegradablepolymer in vivo depends on its molecular weight and degree ofcross-linking; the greater the molecular weight and degree ofcrosslinking, the longer the life. The most highly investigatedbiodegradable polymers are polylactic acid (PLA), polyglycolic acid(PGA), copolymers of PLA and PGA, polyamides, and copolymers ofpolyamides and polyesters. PLA, sometimes referred to as polylactide,undergoes hydrolytic de-esterification to lactic acid, a normal productof muscle metabolism. PGA is chemically related to PLA and is commonlyused for absorbable surgical sutures, as is PLA/PGA copolymer. However,the use of PGA in sustained-release implants has been limited due to itslow solubility in common solvents and subsequent difficulty infabrication of devices.

An advantage of a biodegradable material is the elimination of the needfor surgical removal after it has fulfilled its mission. The appeal ofsuch a material is more than simply for convenience. From a technicalstandpoint, a material which biodegrades gradually and is excreted overtime can offer many unique advantages.

A biodegradable therapeutic agent delivery system has several additionaladvantages: 1) the therapeutic agent release rate is amenable to controlthrough variation of the matrix composition; 2) implantation can be doneat sites difficult or impossible for retrieval; 3) delivery of unstabletherapeutic agents is more practical. This last point is of particularimportance in light of the advances in molecular biology and geneticengineering which have lead to the commercial availability of manypotent bio-macromolecules. The short in vivo half-lives and low GI tractabsorption of these polypeptides render them totally unsuitable forconventional oral or intravenous administration. Also, because thesesubstances are often unstable in buffer, such polypeptides cannot beeffectively delivered by pumping devices.

In its simplest form, a biodegradable therapeutic agent delivery systemconsist of a dispersion of the drug solutes in a polymer matrix. Thetherapeutic agent is released as the polymeric matrix decomposes, orbiodegrades into soluble products which are excreted from the body.Several classes of synthetic polymers, including polyesters (Pitt, etal., in Controlled Release of Bioactive Materials, R. Baker, Ed.,Academic Press, New York, 1980); polyamides (Sidman, et al., Journal ofMembrane Science, 7:227, 1979); polyurethanes (Maser, et al., Journal ofPolymer Science, Polymer Symposium, 66:259, 1979); polyorthoesters(Heller, et al., Polymer Engineering Science, 21:727, 1981); andpolyanhydrides (Leong, et al., Biomaterials, 7:364, 1986) have beenstudied for this purpose.

By far most research has been done on the polyesters of PLA and PLA/PGA.Undoubtedly, this is a consequence of convenience and safetyconsiderations. These polymers are readily available, as they have beenused as biodegradable sutures, and they decompose into non-toxic lacticand glycolic acids. However, a major problem with these polymers is thatit is often difficult to control and predict their degradation.

Polyorthoesters and polyanhydrides have been specifically designed forcontrolled release purposes. While these polymers are promising, theyalso have significant drawbacks. For example, polyorthoesters biodegradein a desirable manner only if additives are included in the matrix. Bytaking advantage of the pH dependence of the rate of orthoestercleavage, preferential hydrolysis at the surface is achieved by eitherthe addition of basic substances to suppress degradation in bulk, or theincorporation of acidic catalysts to promote surface degradation.Unfortunately, these additives often lead to unnecessary complicationsin terms of release behavior and biocompatibility.

The polyanhydrides, on the other hand, are unstable even in the solidstate. In addition, the poor solubility of the hydrophobicpolyanhydrides also render characterization and fabrication difficult.Hence there exists the need for new biodegradable polymers.

The biodegradable matrix of the invention also finds broad utility as atransient prosthetic support in orthopedic applications. For centuries,physicians have attempted to repair and replace various components ofthe skeletal system. These attempts have utilized various kinds ofmaterials including bone, ivory, collagen, wood, metals, alloys,ceramics, glasses, corals, carbons, polymers, and composites ofmaterials as bone prostheses.

Ideally, the bone prosthesis should be a material that is biologicallyinert, readily available, easily adaptable to the site in terms of shapeand size, and replaceable by the host bone. Replacement of the prothesisby the host bone necessitates that the substitute be biodegradable.

The different elastic moduli of the prior art prosthetic implants versusthat of bone often causes cortical bone to atrophy. The theoreticaladvantage of gradual load transfer from the bone plate to the bone andthe elimination of the need for surgical removal after the healing of afracture would make an absorbable osteosynthesis material extremelyuseful. As a temporary support in a load-bearing area of an articularjoint, a resorbable porous material also has the advantage of preventingfurther destruction of cartilage defects and promoting bone andcartilage-forming cells. Hence, a need exists for a biodegradableprosthesis of sufficient post-implantation strength and rigidity toprovide structural support.

SUMMARY OF THE INVENTION

The present invention pertains to a biodegradable composition useful asa structural prosthesis and a therapeutic agent delivery vehicle andmethods for its manufacture and use. The composition comprises abiocompatible poly(phosphoester) matrix, prepared in preselecteddimensions and configurations, which predictably degrades in vivo intonon-toxic residues. The method of using the composition as an implantand prosthesis comprises the step of introducing a specificallyconfigured composition into an individual in vivo at a predeterminedsite.

Although it is preferred that the polymers of the invention bebiodegradable and in matrix form, these characteristics are notessential for the polymers.

The composition of the invention, through its transient in vivopresence, provides a matrix which persists for a period of timesufficient to achieve a medical effect, essentially lacks host toxicityupon degradation, provides mechanical strength, and is readilyfabricated.

DESCRIPTION OF THE DRAWINGS

FIG. 1(a) shows the in vitro release of different pendant R groups whenattached to a poly(2-oxo-1,3,2-dioxaphosphite) backbone matrix. FIG.1(b) compares the release of nitrophenol and aniline from a compositionmatrix system and a pendant system.

FIG. 2 compares the degradation rates of various poly(phosphoesters).

FIG. 3 shows the release rates of non-pendant cortisone from variouspoly(phosphoester) matrices.

FIG. 4 illustrates the release rates of four different drugs form thesame BPA polymer matrix.

DETAILED DESCRIPTION

The present invention is directed to compositions useful as prosthesesand as therapeutic agent delivery vehicles. These compositions comprisea biodegradable, biocompatible class of poly(phosphoesters). Thepolymers are biodegradable because of the hydrolyzable phosphoesters, orP(O)--O--C bond, in the backbone. With the phosphoester the polymers canbe classified as polyphosphates, polyphosphonates, orpolyamidophosphates, depending on the structure of the pendant groups.With the phosphorous atom existing in the trivalent state, the polymerscan be either polyphosphites or polyphosphonites.

Preferred are compositions comprising a biodegradable poly-phosphate orpolyphosphonate matrix which have the general formula: ##STR1## whereinR and R', are preferably organic or organometallic moieties and n isfrom about 10 to about 10⁵.

The R' group can be a therapeutic agent or, alternatively, can beselected from the group consisting of: ##STR2## wherein R₁ is alkyl,halogen, nitro, hydroxyl, amino, carboxyl, alkoxy, or combinationsthereof, R₂ is oxygen or N--CH₃, and a ranges from 2 to 6, b ranges from10 to 100, d ranges from 2 to 16, f ranges from 1 to 6, and m rangesfrom 1 to 2.

Other R' groups that function equivalently to these R' groups are withinthe scope of the invention.

The R group can be a therapeutic agent or, alternatively, can beselected from the group consisting of: ##STR3## wherein R₁ is alkyl,halogen, nitro, hydroxyl, amino, carboxyl, alkoxy, or combinationsthereof, R₃ is ##STR4## and p ranges from 1 to 16.

Other R groups that function equivalently to these R groups are withinthe scope of the invention.

It is also possible for R and R' to be the same or different therapeuticagent.

Other R groups that function equivalently to these R groups are withinthe scope of the invention.

The common synthesis and chemical structures of polyphosphates andpolyphosphonates are shown in Eqs. 1 and 2, respectively. On hydrolysisthe polymers decompose into monomeric phosphates and diols (Eq. 3).However, because of the hydrolytic instability of the phosphorous esterbond, there have not been any commercial applications for these polymers(Sandler, et al., in Polymer Synthesis, Vol. 1, Chap. 13, AcademicPress, New York, 1974). It is this instability, however, which thepresent inventor discovered, renders these polymers attractive forachieving a medical effect for both transient structural prosthesis andtherapeutic agent controlled release applications. ##STR5##

In comparing the hydrolytic reactivity of different carbonyl bonds, thephosphorous ester is comparable to, or slightly more reactive than, thecarboxylic ester. Thus, this water labile linkage provides the basis fora versatile delivery system.

A wide range of degradation rates can be obtained by adjusting thehydrophobicities of the backbones of the polymers and yet thebiodegradability is assured. This can be achieved by varying thefunctional groups R or R'. The combination of a hydrophobic backbone anda hydrophilic linkage also leads to heterogeneous degradation ascleavage is encouraged, but water penetration is resisted.

The polyphosphates and polyphosphonates of the invention show favorablemechanical strength because of the high molecular weights obtainable.Average molecular weight of up to 600,000 has been obtained by aninterfacial polymerization (Sandler, et al., ibid). This high molecularweight leads to transparency, and film and fiber properties. It has alsobeen observed that the P--O--C group provides a plasticizing effect,which lowers the glass transition temperature of the polymer and conferssolubility in organic solvents. Both effects are desirable forfabrication of the composition.

The term "therapeutic agent" as used herein for the compositions of theinvention includes, without limitation, drugs, radioisotopes,immunomodulators, and lectins. Similar substances are within the skillof the art. The term "individual" includes human as well as non-humananimals.

The drugs with which can be incorporated in the compositions of theinvention include non-proteinaceous as well as proteinaceous drugs. Theterm "non-proteinaceous drugs" encompasses compounds which areclassically referred to as drugs such as, for example, mitomycin C,daunorubicin, vinblastine, AZT, and hormones. Similar substances arewithin the skill of the art.

The proteinaceous drugs which can be incorporated in the compositions ofthe invention include immunomodulators and other biological responsemodifiers. The term "biological response modifiers" is meant toencompass substances which are involved in modifying the immune responsein such manner as to enhance the particular desired therapeutic effect,for example, the destruction of the tumor cells. Examples of immuneresponse modifiers include such compounds as lymphokines. Examples oflymphokines include tumor necrosis factor, the interleukins,lymphotoxin, macrophage activating factor, migration inhibition factor,colony stimulating factor and the interferons. Interferons which can beincorporated into the compositions of the invention includealpha-interferon, beta-interferon, and gamma-interferon and theirsubtypes. In addition, peptide or polysaccharide fragments derived fromthese proteinaceous drugs, or independently, can also be incorporated.Also, encompassed by the term "biological response modifiers" aresubstances generally referred to as vaccines wherein a foreignsubstance, usually a pathogenic organism or some fraction thereof, isused to modify the host immune response with respect to the pathogen towhich the vaccine relates. Those of skill in the art will know, or canreadily ascertain, other substances which can act as proteinaceousdrugs.

In using radioisotopes certain isotopes may be more preferable thanothers depending on such factors, for example, as tumor distribution andmass as well as isotope stability and emission. Depending on the type ofmalignancy present come emitters may be preferable to others. Ingeneral, alpha and beta particle-emitting radioisotopes are preferred inimmunotherapy. For example, if an animal has solid tumor foci a highenergy beta emitter capable of penetrating several millimeters oftissue, such as ⁹⁰ Y, may be preferable. On the other hand, if themalignancy consists of single target cells, as in the case of leukemia,a short range, high energy alpha emitter such as ²¹² Bi may bepreferred. Examples of radioisotopes which can be incorporated in thecompositions of the invention for therapeutic purposes are ¹²⁵ I, ¹³¹ I,⁹⁰ Y, ⁶⁷ Cu, ²¹² Bi, ²¹¹ At, ²¹² Pb, ⁴⁷ Sc, ¹⁰⁹ Pd and ¹⁸⁸ Re. Otherradioisotopes which can be incorporated into the compositions of theinvention are within the skill in the art.

Lectins are proteins, usually isolated from plant material, which bindto specific sugar moieties. Many lectins are also able to agglutinatecells and stimulate lymphocytes. Other therapeutic agents which can beused therapeutically with the biodegradable compositions of theinvention are known, or can be easily ascertained, by those of ordinaryskill in the art.

The term "therapeutically effective" as it pertains to the compositionsof the invention means that the therapeutic agent is present atconcentrations sufficient to achieve a particular medical effect forwhich the therapeutic agent is intended. Examples, without limitation,of desirable medical effects which can be attained are chemotherapy,antibiotic therapy, birth control, and regulation of metabolism.

"Therapeutic-agent bearing" as it applies to the compositions of theinvention denotes that the composition incorporates a therapeutic agentwhich is 1) not bound to the polymeric matrix, or 2) bound within thepolymeric backbone matrix, or 3) pendantly bound to the polymericmatrix, or 4) bound within the polymeric backbone matrix and pendantlybound to the polymeric matrix. When the therapeutic agent is not boundto the matrix, then it is merely physically dispersed with the polymermatrix. When the therapeutic agent is bound within the matrix it is partof the poly(phosphoester) backbone (R'). When the therapeutic agent ispendantly attached it is chemically linked through, for example, byionic or covalent bonding, to the side chain (R) of the matrix polymer.In the first two instances the therapeutic agent is released as thematrix biodegrades. The drug can also be released by diffusion throughthe polymeric matrix. In the pendant system, the drug is released as thepolymer-drug bond is cleaved at the bodily tissue.

A combination of more than one therapeutic agent can be incorporatedinto the compositions of the invention. Such multiple incorporation canbe done, for example, 1) by substituting a first therapeutic agent intothe backbone matrix (R') and a second therapeutic agent by pendantattachment (R), 2) by providing mixtures of differentpoly(phosphoesters) which have different agents substituted in thebackbone matrix (R') or at their pendant positions (R), 3) by usingmixtures of unbound therapeutic agents with the poly(phosphoester) whichis then formed into the composition, 4) by use of a copolymer with thegeneral structure ##STR6## wherein m or n can be from about 1 to about99% of the polymer, or 5) by combinations of the above.

The concentration of therapeutic agent in the composition will vary withthe nature of the agent and its physiological role and desiredtherapeutic effect. Thus, for example, the concentration of a hormoneused in providing birth control as a therapeutic effect will likely bedifferent from the concentration of an anti-tumor drug in which thetherapeutic effect is to ameliorate a cell-proliferative disease. In anyevent, the desired concentration in a particular instance for aparticular therapeutic agent is readily ascertainable by one of skill inthe art.

The therapeutic agent loading level for a composition of the inventioncan vary, for example, on whether the therapeutic agent is bound to thepoly(phosphoester) backbone polymer matrix. For those compositions inwhich the therapeutic agent is not bound to the backbone matrix, inwhich the agent is physically disposed with the poly(phosphoester), theconcentration of agent will typically not exceed 50 wt %. Forcompositions in which the therapeutic agent is bound within thepolymeric backbone matrix, or pendantly bound to the polymeric matrix,the drug loading level is up to the stoichiometric ratio of agent permonomeric unit.

The term "transient structural prosthesis" when used to describe thecompositions of the invention means a prosthesis which is biodegradablewith time and provides a structural function in the individual such as,for example, as a vascular graft, suture and bone plate.

A poly(phosphoester) composition of the invention can functionsimultaneously both as a transient structural prosthesis and as atherapeutic agent-bearing composition. An example of this would be asuture bearing a therapeutic agent such as, for example, an antibiotic,or, alternatively, a bone plate incorporating a growth factor.

A novel advantage of the polymers of the invention is the availabilityof functional side groups which allow the chemical linkage oftherapeutic agents to the polymers. For example, drugs with carboxylgroups can be coupled to the phosphorous atom via an ester bond, whichis hydrolyzable (Eq. 4). The rate of therapeutic agent release will thenbe dependent on the hydrolytic cleavage of the polymer therapeutic agentconjugate. This pendant delivery system has the advantage of attaining ahigh drug loading level. Therapeutic agents which exist in the liquidstate can also be accommodated.

Alternatively, therapeutic agents containing two hydroxyl groups can bedirectly incorporated into the backbone of the polymers (Eq. 5). Forinstance, steroids such as estradiol can be reacted withdichlorophosphates to form the polymer. Other therapeutic agents canalso be derivatized for incorporation into the backbone. For instance, adrug with two amino groups can be reacted with the carboxyl group of ahydroxyl carboxylic acid. The hydroxyl groups can then be used to formthe poly(phosphoester). A sustained delivery is then effected byhydrolysis of the polymeric prodrug. ##STR7##

The poly(phosphoester) of the invention can be synthesized using suchpolymerization methods as bulk polymerization, interfacialpolymerization, solution polymerization, and ring opening polymerization(Odian, G., Principles of Polymerization, 2nd ed., John Wiley & Sons,New York, 1981). Using any of these methods, a variety of differentsynthetic polymers having a broad range of mechanical, chemical, andbiodegradable properties are obtained; the differences in properties andcharacteristics are controlled by varying the parameters of reactiontemperatures, reactant concentration, types of solvent, and reactiontime.

The poly(phosphoester) of the invention can range in molecular weightfrom about 2,000 to about 10⁶ containing from about 10 to about 10,000monomeric units.

All of the compositions useful as prostheses or implants are syntheticpoly(phosphoester) compositions which share such characteristics aspredictable and controllable degradation rates, biocompatibility andbiodegradability, mechanical strength, and ease of fabrication.

The rate of biodegradation of the poly(phosphoester) compositions of theinvention may also be controlled by varying the hydrophobicity of thepolymer. The mechanism of predictable degradation preferably relies oneither group R' in the poly(phosphoester) backbone being hydrophobic forexample, an aromatic structure, or, alternatively, if the group R' isnot hydrophobic, for example an aliphatic group, then the group R ispreferably aromatic.

The rates of degradation for each poly(phosphoester) composition aregenerally predictable and constant at a single pH. This permits thecompositions to be introduced into the individual at a variety of tissuesites. This is especially valuable in that a wide variety ofcompositions and devices to meet different, but specific, applicationsmay be composed and configured to meet specific demands, dimensions, andshapes--each of which offers individual, but different, predictableperiods for degradation.

When the composition of the invention is used for long term delivery ofa therapeutic agent a relatively hydrophobic backbone matrix, forexample, containing bisphenol A, is preferred. It is possible to enhancethe degradation rate of the poly(phosphoester) or shorten the functionallife of the device, by introducing hydrophilic or polar groups, into thebackbone matrix. Further, the introduction of methylene groups into thebackbone matrix will usually increase the flexibility of the backboneand decrease the crystallinity of the polymer. Conversely, to obtain amore rigid backbone matrix, for example, when used orthopedically, anaromatic structure, such as a diphenyl group, can be incorporated intothe matrix. Also, the poly(phosphoester) can be crosslinked, forexample, using 1,3,5-trihydroxybenzene or (CH₂ OH)₄ C, to enhance themodulus of the polymer. Similar considerations hold for the structure ofthe side chain (R).

The entire class of poly(phosphoester) are biocompatible andbiodegradable. In view of their intended function as a therapeuticagent-bearing implant or prosthesis to be introduced into a subject invivo, it is desirable that these compositions be essentiallynon-inflammatory, and non-immunogenic.

The use of the poly(phosphoester) of the invention as an implant whichalso functions as a therapeutic agent-bearing polymeric composition, forexample, subcutaneously or in various body cavities, is particularlyuseful in cases where chronic administration of drug over periodsranging from days to years is required. Examples of drugs which can beused in this manner include insulin for diabetes, pilocarpine forglaucoma, immune agents for various diseases and allergies,contraceptive steroids, narcotic antagonists, antibiotics, anticancer,and antihypertensive drugs.

Subcutaneous implantation is currently one of the most popular routesused for sustained drug delivery. This is partly due to the simplicityof the surgical procedures involved in implantation and removal, and therelatively favorable absorption site offered compared to the oral orpercutaneous routes. Surgery could be viewed as a disadvantage, however,depending on the patient and the location and frequency of implantation.It can be avoided in some cases by injecting the implant directly intosubcutaneous tissue, provided the implant is capable of being deliveredthrough a syringe. This is the method used for many of thesustained-release insulin products.

Implantation using a syringe is particularly effective when thecomposition of the invention is in the form of microspheres which can besuspended in a pharmaceutical buffer and introduced via the syringe tothe desired site.

For example, compositions in the form of microspheres incorporatingcortisone could be injected into the region of an inflammatory joint ormuscle.

The use of the biodegradable polymers of the invention to act as amatrix for the release of a therapeutic agent from subcutaneouslyimplanted compositions offers several advantages over prior artcompositions. The most obvious is that no surgical removal of the deviceis necessary after it has fulfilled its function. Also, an additionalmechanism for release of drug is provided by degradation. Completedelivery and, thus, maximal absorption occurs after the device hasdegraded.

The mechanism of release of therapeutic agent from biodegradable slabs,cylinders, and spheres has been described by Hopfenberg (in ControlledRelease Polymeric Formulations, pp. 26-32, Paul, D. R. and Harris, F.W., Eds., American Chemical Society, Washington, D.C., 1976). A simpleexpression describing additive release from these devices where releaseis controlled primarily by matrix degradation is

    M.sub.t /M.sub.∞ =1-[1-k.sub.0 t/C.sub.0 a].sup.n

where n=3 for a sphere, n=2 for a cylinder, and n=1 for a slab. Thesymbol a represents the radius of a sphere or cylinder or thehalf-thickness of a slab. M_(t) and M.sub.∞ are the masses of drugreleased at time t and at infinity, respectively.

Biodegradable subcutaneous implants can also be used, for example, forthe delivery of narcotic antagonists, steroids, and anticancer agents.Narcotic antagonists, such as naltrexone, cyclazocine, and naloxone, aretherapeutically useful in the postdetoxification stage of rehabilitationof drug-dependent patients. Steroids which can be used includecontraceptives (for example, progesterone), anti-inflammatory agents(for example, dexamethasone), and anabolics (for example, estradiol).Anticancer agents which can be used include cyclophosphamide,doxorubicin, and cisplatin.

Intravaginal implants are used for the sustained release ofcontraceptive steroid hormones due to the more favorable site ofabsorption offered by the vaginal mucosa relative to the oral route forthese drugs. First-pass hepatic metabolism, which inactivates manysteroid hormones, and gastrointestinal incompatibility are avoided byusing the vaginal route. In addition, the vaginal route allowsself-insertion ensuring better patient compliance. More stablepoly(phosphoester) are preferred in this usage.

The intrauterine device (IUD) is one of the more popular methods ofcontraception which can utilize the compositions of the invention.Initial investigations involving nonmedicated IUDs revealed that thelarger the device, the more effective it was in preventing pregnancy.Unfortunately, large devices caused increased incidences of uterinecramps, bleeding, and expulsion. The effort to improve intrauterinecontraception and avoid previously demonstrated side effects has led tothe development of medicated IUDs. More stable poly(phosphoester) arepreferred in this usage. Two classes of agents have been used in IUDs ofthis type: contraceptive metals, such as copper, and steroid hormones,such as progesterone.

The compositions of the invention are also useful in the treatment ofglaucoma. Chronic open-angle glaucoma usually requires therapy for thelifetime of the patient with a miotic agent such as pilocarpine, forcontrol of intraocular pressure. Conventional pilocarpine therapyrequires instillation of eyedrops four times a day. Hence, compositionsof the invention incorporating an anti-glaucoma agent such aspilocorpine would require less frequent and more sustainedadministration.

In addition to the embodiments described above, compositions comprisingthe poly(phosphoester) of the invention can be used for agriculturalpurposes. This can be accomplished by substituting for the therapeuticagent, without limitation, a pesticide, a plant growth horomone, afungicide, a fertilizer, and the like, others of which are known orreadily ascertainable to those of skill in the art.

The above disclosure generally describes the present invention. Afurther understanding can be obtained by reference to the followingspecific examples which are provided herein for purposes of illustrationonly, and are not intended to be limiting unless otherwise specified.

EXAMPLE 1 General Polymer Synthesis Techniques

Four different methods were used for the synthesis of thephosphorus-containing polymers: bulk polycondensation, solutionpolymerization, interfacial polycondensation, and ring-openingpolymerization. In these syntheses, care was taken to eliminate tracesof moisture from the system. The reaction vessels were carefully driedand purged with dry nitrogen before use. The nitrogen stream was passedthrough a Deoxo purifier for oxygen removal. The polymerization, exceptin the case of interfacial polycondensation, was conducted undernitrogen sweep. All reactants were fractionally distilled under vacuumor recrystallized before use. In particular, the phosphorus diacidchlorides were freshly distilled before each experiment. Solvents weredried over molecular sieves. The phase transfer catalysts ofcetyltrimethylammonium chloride and crown ether 18 were used for theinterfacial polycondensation. Lewis acids of ferric chloride andmagnesium chloride were used for melt-polycondensation. For ring-openingpolymerization, t-BuOK or (i-C₄ H₉)₃ Al were used as initiators. Inreactions involving diols oxidizable to quinones in base the procedureswere performed in the dark, and small amounts of sodium hydrosulfitewere added to the interfacial polycondensation to prevent oxidation ofthe diol.

A. Melt-Polycondensation:

In melt, or bulk, polycondensation the phosphonic or phosphoricdichloride is mixed with the diol in the absence of solvent. A Lewisacid catalyst (FeCl₃, MgCl₂, etc.) is added and the mixture is heated,often under vacuum or nitrogen blanket, to remove the Hcl formed. Thesesomewhat vigorous conditions can lead to chain acidolysis (or hydrolysisif water is present). Unwanted, thermally-induced side reactions such asadventitious crosslinking can also occur if the polymer backbone issusceptible to hydrogen atom abstraction or oxidation with subsequentmacroradical recombination. On the positive side, this technique avoidssolvents and large amounts of other additives, thus making purificationmore straightforward. It can also provide polymers of reasonablemolecular weight.

B. Solution-Polycondensation:

Solution polycondensation requires that both the diol and the phosphoruscomponent be soluble in a common solvent. Typically, a chlorinatedorganic solvent was used and the reaction run in the presence of astoichiometric amount of an acid acceptor. The product was then isolatedfrom the solution by precipitation and purified to remove thehydrochloride salt. Although longer reaction times may be necessary,generally much milder conditions are used relative to bulk-reactions.More sensitive functionality can thus be incorporated using thistechnique.

C. Interfacial-Polycondensation:

Interfacial polycondensation potentially yields high molecular weightsfor these polymers at high reaction rates. Since the interfacialtechnique is a non-equilibrium method, the critical dependence of highmolecular weight on exact stoichiometric equivalence between diol anddichloridate inherent in bulk and solution methods is removed. Thelimitation of this method is the hydrolysis of the acid chloride in thealkaline aqueous phase. Phosphoro-dichloridates which have somesolubility in water are generally subject to hydrolysis rather thanpolymerization.

D. Ring Opening:

Ring-opening polymerization of phosphorus-containing monomers wasperformed using the technique disclosed in Lapienis, et al., Journal ofPolymer Science, Part A: Polymer Chemistry, 25:1729, 1987 and Pretula,et al., Macromolecules, 19:1797, 1986. This technique is particularlyuseful in producing high molecular weight polymers.

EXAMPLE 2 Preparation of Poly(Phosphoesters)

A Using the melt-condensation technique, a poly(phosphoester) having thestructure disclosed in Equation 6 was produced. Ethylphosphorodichloridate was slowly added to a magnetically stirred mixtureof an equimolar amount of ethylene glycol containing 2 mole percent ofFeCl₃ cooled to -20° C. The flask was connected to a vacuum pump througha trap to remove HCl. When the addition was complete, the temperaturewas gradually raised to 120° C. over a seven hour period. The mass wasthen cooled to room temperature, dissolved in methanol, and precipitatedinto ether. ##STR8##

B. Using the solution-polycondensation technique, a poly(phosphoester)with the structure disclosed in Equation 7 was produced.

A solution of recrystallized bisphenol-A (10.0 g, 43.8 mmol) and driedpyridine (7.62 g, 2.2 equiv.) in 100 ml of dried methylene chloride wascooled to 5° C. in a 500 ml three-necked flask equipped with a paddlestirrer, thermometer, and gas inlet and exit tubes. Under positivepressure of dry nitrogen, a solution of 7.14 g (43.8 mmol) of freshlydistilled ethyl phosphorodichloridate in 25 ml of methylene chloride wasadded from an addition funnel over a period of 30 minutes. An increasein viscosity was noted during the addition. When the addition wascomplete, the temperature was allowed to rise to 25° C. and stirring wascontinued under nitrogen for 18 hours. The precipitate of pyridinehydrochloride was removed by filtration and the filtrate was washedtwice with 40 ml of distilled water. After drying over CaCl₂, themethylene chloride solution was concentrated and precipitated into 500ml of petroleum ether. The oily isolated was dried on a vacuum line atroom temperature for 16 hours to give 8.42 g (60.4% yield) of thepoly(phosphate) as a crisp white foam having M_(w) =17,000 (by GPCrelative to polystyrene in chloroform). ##STR9##

C. The poly(phosphoester) of Equation 8 was produced using theinterfacial polycondensation technique.

A solution of recrystallized bisphenol-A (10.0 g, 43.8 mmol) and sodiumhydroxide (3.66 g, 1.04 equiv.) in 65 ml of distilled water wasprepared; 1.12 g (2 mole percent) of a 25% aqueous solution ofcetyltrimethylammonium chloride (CTMAC) was then added with stirring.Separately a solution of phenylphosphonodichloridate (8.59 g, 43.8 mmol)in 60 ml of dried methylene chloride was prepared in a dropping funneland kept under nitrogen. Both of these solutions were then cooled to 0°C. The aqueous solution was transferred to the jar of a 1 L Waringcommercial blender; low speed mixing was begun immediately. The organicsolution was run into the agitated solution from the funnel through ahole in the cap over a one-minute period. The mixture was blended forfour minutes, producing a thick, milky emulsion with a temperature of35° C. After separating the layers in a separatory funnel, the lowerorganic layer was washed with 30 ml of water, dried over CaCl₂, andprecipitated into 750 ml of petroleum ether to give a fibrous, powderysolid. The solid was isolated by filtration, reprecipitated in the samemanner, isolated again, and dried on a vacuum line at room temperaturefor 16 hr to give the polyphosphonate (15.1 g, 98.4%) as a fine powder.##STR10##

D. The ring-opening technique was used to produce the poly(phosphoester)shown in Equation 9. Using dioxaphosphorinane at a concentration of 7.0mol/L in methylene chloride, a polymer with a number average molecularweight of over 100,000 was obtained as a white, powdery material inabout 50% yield when triisobutylaluminum (0.03M) was used as theinitiator at 25° C. after a 24 hour reaction (Eq. 9). The difficulty ofthis technique is the preparation of the pure cyclic monomers. In orderto maintain a favorable thermodynamic driving force for the ring-openingreaction, the monomer is confined to aliphatic and non-bulky groups. Thecyclic monomer also should not contain acidic protons. ##STR11##

Additional examples of some of the poly(phosphoesters) which have beensynthesized using the above techniques and their properties are shown inTable 1.

                                      TABLE 1                                     __________________________________________________________________________    Polymer                                                                            R       R'                                                                              Method                                                                             Properties                                                __________________________________________________________________________    I    OC.sub.2 H.sub.5                                                                      1 A    dark brown solid, swells in hot water                          OC.sub.2 H.sub.5                                                                      1 C    white powder; M.sub.n = 3879, M.sub.w = 35365,                                T.sub.s = 60-70° C.                                     OC.sub.2 H.sub.5                                                                      1 B    M.sub.n = 3920                                            II   OC.sub.2 H.sub.5                                                                      2 C    T.sub.m = 110-130° C.; solution in chloroform      III  OC.sub.2 H.sub.5                                                                      3 C    [ ] = 0.16 dL/g, soluble in DMF                           IV   OC.sub.2 H.sub.5                                                                      4a                                                                              A    waxy solid, T.sub.m = 30-35° C., soluble in pH                         7.4                                                                           phosphate buffer, slow decomposition in                                       air (spongy)                                              V    OC.sub.2 H.sub.5                                                                      4b                                                                              A    solid swells up to 560% in 48 hours in                                        pH 7.4 phosphate buffer, swells in MeOH                                       and chloroform, T.sub.m = 140-220° C.              VI   OC.sub.2 H.sub.5                                                                      4c                                                                              A    swells in buffer, T.sub.m = 90° C.                 VII  OC.sub.2 H.sub.5                                                                      4c                                                                              A    water soluble, T.sub.m = 55-65° C.                 VIII C.sub.6 H.sub.5                                                                       1 C    M.sub.n = 4917, M.sub.w = 33867                           IX   OC.sub.6 H.sub.5                                                                      1 C    M.sub.n = 3745, M.sub.w = 34860                           X    OC.sub.6 H.sub.5 (NO.sub.2)                                                           1 C    yellow sticky material                                    __________________________________________________________________________     A = meltcondensation with MgCl.sub.2 as catalyst                              B = solution polymerization in refluxing methylene chloride                   C = aqueous interfacial condensation (CH.sub.2 Cl.sub.2H.sub.2 O) with        phase transfer catalysts                                                      ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                

EXAMPLE 3 Comparative Release Rates of Compounds from Pendant and MatrixSystems

Poly(phosphoester) compositions were prepared which contained benzoicacid, aniline, thiophenol, or p-nitrophenol in pendant position incombination with an aliphatic backbone, as shown in Equation 10 below.##STR16##

R=benzoic acid, aniline, thiophenol, or p-nitrophenol

The ring-opening polymerization technique was used to preparepoly(2-chloro-2-oxo-1,3,2-dioxaphosphite). To prepare the cyclic monomer2-hydro-2-oxo-1,3,2-dioxaphosphite, a solution (100 ml) of1,3-propanediol (0.165 mole) and triethylamine (TEA) (0.33 mole) inbenzene was added dropwise to vigorously stirred anhydrous benzene (200ml) at 0° C. under nitrogen atmosphere. Phosphorus trichloride (0.165mole) in anhydrous benzene (200 ml) was then added. After a reaction oftwo hours and the TEA HCl salt filtered off, a mixture of water (0.2mole), TEA (0.2 mole), and tetrahydrofuran (10 ml) were added dropwise.After two hours of vigorous agitation, the solvent was removed underreduced pressure. The residue was separated by flash chromatographyusing silica as the packing material and chloroform/toluene (50:50) asthe mobile phase. The purity of the monomer was checked by thin layerchromatography (TLC). The TLC plates were developed by iodine vapor forvisualization.

The polymers were synthesized by anionic polymerization of2-hydro-2-oxo-1,3,2-oxaphosphorinane. The anionic polymerization wasconducted in methylene chloride at -15° C. for 48 hours under nitrogenatmosphere. A 1 mole % of i-Bu₃ Al was used as the anionic initiator.The polymer was isolated by repeated precipitation into dried benzene.Chlorination of the polymer was achieved by passing dried chlorinethrough a solution of the polymer in methylene chloride until apersistent yellow color was obtained (about three hours). The excesschlorine was then removed by vacuum at room temperature. The polymerswas characterized by GPC, intrinsic viscosity, FT-IR, and FT-NMR.

After chlorination, the compounds were linked to the side chain of thepolymer via dehydrochlorination. The chemical structures containingdifferent R groups were all confirmed by FTIR and UV spectrophotometry.FIG. 1a shows the in vitro release of the R groups from polymer.

The drug release rate was dependent on the stability of the linkagebond. For instance, benzoic acid was bound to the polymer via aphosphoric anhydride bond, which is extremely water labile.Consequently, a high release rate was seen. The model drugs are allwater soluble compounds, which in a diffusion-controlled release systemwould be depleted very quickly.

Shown in FIG. 1b is the comparison of the release of p-nitrophenol andaniline from a matrix system (in which the drug is just physicallydispersed in the polymer and compression molded into a disc) and thatreleased from the pendant system (in which the polymer-drug conjugatesare compression molded to the same dimension). The time it took for 50%of the drug to be released from the polymer-drug conjugate wassignificantly longer, showing that the pendant system is indeed capableof prolonging the release of hydrophilic drugs through a phosphate esteror a phosphoroamide bond.

EXAMPLE 4 Comparison of Degradation Rates of Various BPA Polymers

Various poly(phosphoesters) were prepared having a bisphenol A (BPA)backbone and their rates of in vitro degradation compared.

These polymers were prepared in a manner similar to that disclosed inExample 1 B or C except for the substitutions to the phosphochloridate.The four side chains of Table 2 were commercially available from AldrichChemicals.

In order to use side chains of other structures it is possible to startwith the phosphorochloride of ##STR17## where R is the desiredstructure. The monomer can be obtained either commercially or customsynthesized. Such synthesis can be carried out, for example, by reactingphosphorous oxychloride with the desired structure in the presence of aacid acceptor in an organic solvent, according to the general equation:##STR18## The polymers prepared had the structures indicated in Table 2.

                  TABLE 2                                                         ______________________________________                                         ##STR19##                                                                    R                     Designation                                             ______________________________________                                        OC.sub.2 H.sub.5      BPA-EOP                                                 C.sub.2 H.sub.5       BPA-EP                                                   ##STR20##            PBA-POP                                                  ##STR21##            BPA-PP                                                  ______________________________________                                    

These polymers were then placed in pH 12 phosphate buffer and theirrelative rates of degradation determined.

The degradation experiments were conducted in 0.1M phosphate buffer (pH12). The polymers were compression molded into discs (1 cm×2 mm), placedin 50 ml of pH 12 buffer, and incubated at 37° C. The release kineticswere followed by measuring the concentrations of the buffer solution byHPLC. The weight loss of the discs as a function of time was alsorecorded.

The results are illustrated in FIG. 2. As expected, the hydrolysis wasbase catalyzed. In pH 7.4 buffer at 37° C.₉ BPA-EOP lost less than 5% ofits weight in 10 days. In a 0.1M NaOH solution at 37° C.₉ the polymercompletely decomposed in less than one week.

EXAMPLE 5 Comparison of Non-Pendant Drug Release Rates from BPA Polymers

Poly(phosphoesters) with a bisphenol A backbone and different sidechains were prepared as described in Example 4 and compared in terms oftheir in vitro release of different drugs.

In a first experiment compositions of BPA-PP, BPA-POP, BPA-EP, andBPA-EOP incorporating cortisone or lidocaine were compared.

Drugs were incorporated into the matrix by compression molding. Thepolymer was ground and sieved into a particle size range below 90microns. Drugs were sieved to the same particle size range and blendedin a Vortex mixer with the polymer powder. The mixture was pressed intoa disc (10 mm×2 mm) through a mold, at a pressure of 150 Kpsi and roomtemperature for 10 min. Such a high molding pressure is useful informing a compact matrix for desirable sustained release. The molds werespecifically made with carbon and heat treated plungers to withstand thehigh pressure. The poly(phosphoester)-drug conjugates are similarlymolded for implantation.

A solvent evaporation technique was used to prepare the microspheres. Asolution of 2 g of polymer and 0.4 g of drug in 20 ml of methylenechloride was prepared. The mixture was emulsified in 150 ml of watercontaining 0.5 wt % of poly(vinyl alcohol) in a homogenizer. Themethylene chloride in the emulsion was evaporated over a period of onehour at room temperature at a reduced pressure of 40 mm Hg. Themicrospheres thus obtained were quickly washed with cold water andfiltered. After drying, the microspheres were sieved to a narrow sizefraction before use. This technique can be used to encapsulate, forexample, such organic substances as sucrose and nerve growth factor.

Release experiments were conducted in a 0.1M pH 7.4 phosphate buffercontaining 0.02 wt % of gentamicin sulfate to inhibit bacterial growth.The drug-loaded matrices were placed in 10 ml of buffer in 20 ml vialsand incubated at 37° C. The release kinetics were followed by measuringthe concentrations of the buffer solutions by scintillation counting andhigh pressure liquid chromatography (HPLC). HPLC analysis was used todetermine the degradation rate of the matrix and to check the chemicalpurity of the drug. To approximate perfect sink conditions, thefrequency of replacement of the buffer solutions was adjusted during thecourse of the release study to ensure that the drug concentration inbuffer was below 20% of its saturation value. In situations where therelease rates are rapid (100 percent release in less than 2 days) andwhen dealing with microspheres, the experiment was conducted in a flowsystem. The matrices or the microspheres were placed in a glass vialequipped with a glass filter and Teflon stopcock in the bottom. Acounter-gravitational flow of 0.1M pH 7.4 phosphate buffer was passedthrough the sample at a rate of 0.5 ml/min. Both the buffer reservoirand the release vessel were immersed in a 37° C. bath. The eluent wascollected every hour and subjected to chromatographic andspectrophotometric analyses.

The release kinetics are shown for cortisone in FIG. 3. The dataindicate that the release rate was dependent on the chemical structureof the side chain (R). This is the first study which demonstratessystematically that the variation of the side chain of a biodegradablepolymer can control the release rates. The EOP and EP side chainsgenerally give faster release rates because they are less hydrophobicthan the POP and PP structures. Noteworthy is the constant release ofcortisone from the polymers.

In a second experiment, the release kinetics of various non-pendantdrugs were measured for BPA-EOP derived matrix compositions. As shown inFIG. 4, all four drugs were release in intact form from the polymer asdetermined by HPLC. These release profiles show that, in general, drugsof higher water solubility have higher release rates.

EXAMPLE 6 Preparation of Pendant 5-Fluorouracil Compositions

A mixture of 5-FU (7 mmole) and 1,1,1,3,3,3-hexamethyldisilazane (30 ml)were heated at reflux temperature for 20 hours in the presence of acatalytic amount of ammonium sulphate to derivatize 5-FU. Evaporation ofthe mixture under reduced pressure resulted in the formation of2,4-bis-o-trimethylsilyl-5-fluorouracil. To obtain the finalpolymer-drug conjugate, the chlorinated poly(phosphoester) (5 g) inmethylene chloride (20 ml) was reacted with the 5-FU derivative in thepresence of a stoichiometric amount of pyridine. After stirring for 18hours at room temperature, 15 ml of methanol was added. Afterevaporation of the solvent, the residue was redissolved in dimethylformamide and repeatedly precipitated into acetone. Linking ofiodoaminopurine (IAP) to the polymer can be achieved in a similar mannerby taking advantage of the facile reaction between the primary amine ofthe drug and the chlorine in the side chain of the polymer.

In the in vitro release studies (as in Example 5), a sustained releaseof 5-FU was observed for at least 7 days and chemical integrity of the5-FU was confirmed by HPLC. This release rate is far superior to similarstudies with 5-FU pendently attached to a polyhydride carrier wherenearly complete release occurred after only 2 days.

The invention now being fully described, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade without departing from the spirit or scope of the invention.

I claim:
 1. A polymer represented by the formula: ##STR22## wherein nranges from about 10 to about 10⁵, R is a therapeutic agent capable ofbeing released in a physiological environment, and R' is selected fromthe group consisting of: ##STR23## wherein R₁ is alkyl, halogen, nitro,hydroxyl, amino, carboxyl, alkoxy, or combinations thereof, R₂ is oxygenor N--CH₃ and a ranges from 2 to 6, b ranges from 10 to 100, d rangesfrom 2 to 16, f ranges form 1 to 6, and m ranges from 1 to
 2. 2. Apolymer represented by the formula: ##STR24## wherein n ranges fromabout 10 to about 10⁵, R' is a therapeutic agent capable of beingreleased in a physiological environment, and R is selected form thegroup consisting of: ##STR25## wherein R₁ is alkyl, halogen, nitro,hydroxyl, amino carboxyl, alkoxy, or combinations thereof, R₃ is##STR26## and p ranges from 1 to
 16. 3. A polymer represented by theformula: ##STR27## wherein n=10 to 10⁵, and both R and R' aretherapeutic agents capable of being released in a physiologicalenvironment.
 4. The polymer of claim 3, wherein R is a first therapeuticagent and R' is a second therapeutic agent.
 5. The polymer as in any ofclaims 1-3, wherein said therapeutic agent is selected from the groupconsisting of one or more of the following: a drug, a radioisotope, abiological response modifier, a lectin, or mixtures thereof.
 6. Apolymer represented by the formula: ##STR28## wherein n ranges fromabout 10 to about 10⁵, R' is selected from the group consisting of:##STR29## R is selected from the group consisting of: ##STR30## whereinR, is alkyl, halogen, nitro, hydroxyl, amino, carboxyl, alkoxy, orcombinations thereof, R₂ is oxygen or N--CH₃, ##STR31## A ranges from 2to 6, B ranges from 10 to 100, D ranges from 2 to 16, F ranges from 1 to6, M ranges from 1 to 2, and P ranges from 1 to 16.